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Introduction: Pulmonary embolism (PE) is a life-threatening condition associated with in-hospital mortality, especially among patients with intermediate- and high-risk PE. Treatment options include systemic thrombolysis, catheter-directed thrombolysis (CDT), and mechanical thrombectomy (MT). Data directly comparing outcomes among these modalities are limited. Systemic thrombolysis carries increased bleeding risk, while CDT and thrombectomy may offer improved safety. This study compares morbidity, mortality, and safety outcomes across these treatments. Methods: This single-center retrospective chart review included adults with intermediate- or high-risk PE treated with systemic thrombolysis, CDT, or MT from 2020 through 2024. The primary outcome was in-hospital mortality. Secondary outcomes included ICU length of stay (LOS) and major bleeding. Outcomes compared systemic thrombolysis to patients who received either MT or CDT. A subgroup analysis described outcomes between MT and CT cohorts. Mann-Whitney U and Fisher’s exact tests were used for statistical analysis. Results: Of the 513 patients screened, 27 patients were included. 9 received systemic thrombolysis, 12 underwent MT, and 6 received CDT. Patients who received systemic thrombolysis had a median age of 56 years, PE Severity Index (PESI) score of 86, and 56% had high-risk PE. Patients who received CDT or MT had a median age of 62 years, PESI score of 84, and 40% had high-risk PE. Systemic thrombolysis was associated with a higher in-hospital mortality compared to CDT and MT (n(%), 5(56) vs 0(0); p=0.0016) with no difference in ICU LOS (median days, 3.5 vs. 3; p = 0.5067). No major bleeding events occurred in either cohort. The subgroup analysis comparing CDT and MT found no difference in any mortality, morbidity, or safety outcomes. Conclusions: This study found increased risk of mortality with systemic thrombolysis compared to MT or CDT with no difference in ICU LOS or major bleeding. Results should be interpreted as exploratory due to higher number of patients in the systemic thrombolysis cohort considered to have high-risk PE. Providers should consider the risks and benefits of systemic thrombolysis, CDT, and mechanical thrombectomy. Further studies are needed to identify the safest and most effective treatment for intermediate- and high-risk PE.